Biosensor system with integrated microneedle

ABSTRACT

A biosensor system package includes: a transistor structure in a semiconductor layer having a front side and a back side, the transistor structure comprising a channel region; a buried oxide (BOX) layer on the back side of the semiconductor layer, wherein the buried oxide layer has an opening on the back side of the channel region, and an interface layer covers the back side over the channel region; a multi-layer interconnect (MLI) structure on the front side of the semiconductor layer, the transistor structure being electrically connected to the MLI structure; and a cap structure attached to the buried oxide layer, the cap structure comprising a microneedle.

PRIORITY CLAIM AND CROSS-REFERENCE

This application is a divisional of U.S. patent application Ser. No.17/104,059, filed Nov. 25, 2020, which claims the benefit of U.S.Provisional Application No. 62/967,850, filed Jan. 30, 2020, thedisclosure of which is hereby incorporated by reference in its entirety.

BACKGROUND

Biosensors are devices for sensing and detecting biomolecules andoperate on the basis of electronic, electrochemical, optical, andmechanical detection principles. Biosensors that include transistors aresensors that electrically sense charges, photons, and mechanicalproperties of bio-entities or biomolecules. The detection can beperformed by detecting the bio-entities or biomolecules themselves, orthrough interaction and reaction between specified reactants andbio-entities/biomolecules. Such biosensors can be manufactured usingsemiconductor processes, can quickly convert electric signals, and canbe easily applied to integrated circuits (ICs) andmicroelectromechanical systems (MEMS).

BRIEF DESCRIPTION OF THE DRAWINGS

Aspects of the present disclosure are best understood from the followingdetailed description when read with the accompanying figures. It isnoted that, in accordance with the standard practice in the industry,various features are not drawn to scale. In fact, the dimensions of thevarious features may be arbitrarily increased or reduced for clarity ofdiscussion.

FIG. 1A is a block diagram of an example biosensor system in accordancewith some embodiments.

FIG. 1B is a schematic diagram of an example biosensor used in thebiosensor system of FIG. 1A in accordance with some embodiments.

FIG. 2A is a cross-sectional diagram illustrating a biosensor systempackage in accordance with some embodiments.

FIG. 2B is a cross-sectional diagram illustrating another biosensorsystem package 200 b in accordance with some embodiments.

FIG. 3A is a top view of an integrated continuous biomarker monitoringand treatment chip in accordance with some embodiments.

FIG. 3B is a cross-sectional diagram illustrating the cross section ofthe integrated continuous biomarker monitoring and treatment chip alonga line A-A′ of FIG. 3A in accordance with some embodiments.

FIG. 3C is a cross-sectional diagram illustrating the cross section ofthe integrated continuous biomarker monitoring and treatment chip alonga line B-B′ of FIG. 3A in accordance with some embodiments.

FIG. 3D is a cross-sectional diagram illustrating the cross section ofthe integrated continuous biomarker monitoring and treatment chip alonga line C-C′ of FIG. 3A in accordance with some embodiments.

FIG. 3E is a diagram illustrating the use of the integrated continuousbiomarker monitoring and treatment chip of FIG. 3A in accordance withsome embodiments.

FIG. 3F is a flowchart illustrating a method of operating the integratedcontinuous biomarker monitoring and treatment chip of FIG. 3A inaccordance with some embodiments.

FIG. 4A is a top view of a simultaneously biomarker monitoring and drugreleasing treatment chip and the application thereof in accordance withsome embodiments.

FIG. 4B is a flowchart illustrating a method for simultaneous biomarkermonitoring and drug releasing treatment chip of FIG. 4A in accordancewith some embodiments.

FIG. 5A is a top view of another integrated continuous biomarkermonitoring and treatment chip in accordance with some embodiments.

FIG. 5B is a cross-sectional diagram illustrating the cross section ofthe integrated continuous biomarker monitoring and treatment chip alonga line A-A′ of FIG. 5A in accordance with some embodiments.

FIG. 5C is a cross-sectional diagram illustrating the cross section ofthe integrated continuous biomarker monitoring and treatment chip alonga line B-B′ of FIG. 5A in accordance with some embodiments.

FIG. 5D is a cross-sectional diagram illustrating the cross section ofthe integrated continuous biomarker monitoring and treatment chip alonga line C-C′ of FIG. 5A in accordance with some embodiments.

FIG. 5E is a diagram illustrating the use of the integrated continuousbiomarker monitoring and treatment chip of FIG. 5A in accordance withsome embodiments.

FIG. 5F is a flowchart illustrating a method for continuous biomarkermonitoring in accordance with some embodiments.

FIG. 5G is a diagram illustrating the use of the integrated continuousbiomarker monitoring and treatment chip of FIG. 5A in accordance withsome embodiments.

FIG. 5H is a flowchart illustrating a method for continuous biomarkermonitoring with closed-loop drug releasing treatment in accordance withsome embodiments.

FIG. 6A and FIG. 6B are flowcharts illustrating a method of fabricatingthe biosensor system packages of FIG. 2A and FIG. 2B, respectively, inaccordance with some embodiments.

FIG. 6C is a flowchart illustrating the step 624 of the method of FIG.6A and FIG. 6B in accordance with some embodiments.

FIG. 6D is a flowchart illustrating the step 636 of the method of FIG.6A and FIG. 6B in accordance with some embodiments.

FIG. 6E is another flowchart illustrating the step 636 of the method ofFIG. 6A and FIG. 6B in accordance with some embodiments.

FIGS. 7-38 are cross-sectional diagrams illustrating the biosensorsystem package constructed according to one or more steps of the methodof FIG. 6A and FIG. 6B in accordance with some embodiments.

DETAILED DESCRIPTION

The following disclosure provides many different embodiments, orexamples, for implementing different features of the provided subjectmatter. Specific examples of components and arrangements are describedbelow to simplify the present disclosure. These are, of course, merelyexamples and are not intended to be limiting. For example, the formationof a first feature over or on a second feature in the description thatfollows may include embodiments in which the first and second featuresare formed in direct contact, and may also include embodiments in whichadditional features may be formed between the first and second features,such that the first and second features may not be in direct contact. Inaddition, the present disclosure may repeat reference numerals and/orletters in the various examples. This repetition is for the purpose ofsimplicity and clarity and does not in itself dictate a relationshipbetween the various embodiments and/or configurations discussed.

Further, spatially relative terms, such as “beneath,” “below,” “lower,”“above,” “upper” and the like, may be used herein for ease ofdescription to describe one element or feature's relationship to anotherelement(s) or feature(s) as illustrated in the figures. The spatiallyrelative terms are intended to encompass different orientations of thedevice in use or operation in addition to the orientation depicted inthe figures. The apparatus may be otherwise oriented (rotated 90 degreesor at other orientations) and the spatially relative descriptors usedherein may likewise be interpreted accordingly.

In general, the term “bioFET” as used herein refers to a field-effecttransistor (FET) that includes a layer of immobilized capture reagentsthat act as surface receptors to detect the presence of a target analyteof biological origin. A bioFET is a field-effect sensor with asemiconductor transducer, according to some embodiments. One advantageof bioFETs is the prospect of label-free operation. Specifically,bioFETs enable the avoidance of costly and time-consuming labelingoperations such as the labeling of an analyte with, for instance,fluorescent or radioactive probes. The analytes for detection by abioFET will normally be of biological origin, such as—withoutlimitation—proteins, carbohydrates, lipids, tissue fragments, orportions thereof. A BioFET can be part of a broader genus of FET sensorsthat may also detect any chemical compound (known in the art as a“ChemFET”) or any other element, including ions such as protons ormetallic ions (known in the art as an “ISFET”). This disclosure appliesto all types of FET-based sensors (“FET sensor”).

“Capture reagent,” as used herein, is a molecule or compound capable ofbinding the target analyte or target reagent, which can be directly orindirectly attached to a substantially solid material. The capturereagent can be a chemical, and specifically any substance for whichthere exists a naturally occurring target analyte (e.g., an antibody,polypeptide, DNA, RNA, cell, virus, etc.) or for which a target analytecan be prepared, and the capture reagent can bind to one or more targetanalytes in an assay.

“Target analyte,” as used herein, is the substance to be detected in thetest sample using the present disclosure. The target analyte can be achemical, and specifically any substance for which there exists anaturally occurring capture reagent (e.g., an antibody, polypeptide,DNA, RNA, cell, virus, etc.) or for which a capture reagent can beprepared, and the target analyte can bind to one or more capturereagents in an assay. “Target analyte” also includes any antigenicsubstances, antibodies, or combinations thereof. The target analyte caninclude a protein, a peptide, an amino acid, a carbohydrate, a hormone,a steroid, a vitamin, a drug including those administered fortherapeutic purposes as well as those administered for illicit purposes,a bacterium, a virus, and metabolites of or antibodies to any of theabove substances.

“Biomarker,” as used herein, means a measurable indicator of theseverity or presence of some disease state. More generally a biomarkeris anything that can be used as an indicator of a particular diseasestate or some other physiological state of an organism. A biomarker canbe a substance that is introduced into an organism as a means to examineorgan function or other aspects of health. For example, rubidiumchloride is used in isotopic labeling to evaluate perfusion of heartmuscle. It can also be a substance whose detection indicates aparticular disease state, for example, the presence of an antibody mayindicate an infection. More specifically, a biomarker indicates a changein expression or state of a protein that correlates with the risk orprogression of a disease, or with the susceptibility of the disease to agiven treatment. Biomarkers can be characteristic biological propertiesor molecules that can be detected and measured in parts of the body likethe blood or tissue. They may indicate either normal or diseasedprocesses in the body. Biomarkers can be specific cells, molecules, orgenes, gene products, enzymes, or hormones. Complex organ functions orgeneral characteristic changes in biological structures can also serveas biomarkers.

“Test sample,” as used herein, means the composition, solution,substance, gas, or liquid containing the target analyte to be detectedand assayed using the present disclosure. The test sample can containother components besides the target analyte, can have the physicalattributes of a liquid, or a gas, and can be of any size or volume,including for example, a moving stream of liquid or gas. The test samplecan contain any substances other than the target analyte as long as theother substances do not interfere with the binding of the target analytewith the capture reagent or the specific binding of the first bindingmember to the second binding member. Examples of test samples include,but are not limited to, naturally-occurring and non-naturally occurringsamples or combinations thereof. Naturally-occurring test samples can besynthetic or synthesized. Naturally-occurring test samples include bodyor bodily fluids isolated from anywhere in or on the body of a subject,including, but not limited to, blood, plasma, serum, urine, saliva orsputum, spinal fluid, cerebrospinal fluid, pleural fluid, nippleaspirates, lymph fluid, fluid of the respiratory, intestinal, andgenitourinary tracts, tear fluid, saliva, breast milk, fluid from thelymphatic system, semen, cerebrospinal fluid, intra-organ system fluid,ascitic fluid, tumor cyst fluid, amniotic fluid and combinationsthereof, and environmental samples such as ground water or waste water,soil extracts, air, and pesticide residues or food-related samples.

Detected substances can include, for example, nucleic acids (includingDNA and RNA), hormones, different pathogens (including a biologicalagent that causes disease or illness to its host, such as a virus (e.g.,H7N9 or HIV), a protozoan (e.g., Plasmodium-causing malaria), or abacteria (e.g., E. coli or Mycobacterium tuberculosis)), proteins,antibodies, various drugs or therapeutics or other chemical orbiological substances, including hydrogen or other ions, non-ionicmolecules or compounds, polysaccharides, small chemical compounds suchas chemical combinatorial library members, and the like. Detected ordetermined parameters may include, but are not limited to, pH changes,lactose changes, changing concentration, particles per unit time where afluid flows over the device for a period of time to detect particles(e.g., particles that are sparse), and other parameters.

As used herein, the term “immobilized,” when used with respect to, forexample, a capture reagent, includes substantially attaching the capturereagent at a molecular level to a surface. For example, a capturereagent may be immobilized to a surface of the substrate material usingadsorption techniques including non-covalent interactions (e.g.,electrostatic forces, van der Waals, and dehydration of hydrophobicinterfaces) and covalent binding techniques where functional groups orlinkers facilitate attaching the capture reagent to the surface.Immobilizing a capture reagent to a surface of a substrate material maybe based on the properties of the substrate surface, the medium carryingthe capture reagent, and the properties of the capture reagent. In somecases, a substrate surface may be first modified to have functionalgroups bound to the surface. The functional groups may then bind tobiomolecules or biological or chemical substances to immobilize themthereon.

A biosensor system includes, among other things, a sensing chip and amicroneedle. The microneedle and the sensing chip often are fabricatedseparately and later assembled manually, which is not a scalablemanufacturing solution.

In accordance with some embodiments, a wafer-level packaging solution tofabricate sensing chips and cap structures with microneedles together isprovided. The solution may be used for biomarker monitoring and/or drugdelivery. Since microneedles and sensing chips are fabricated together,there is no need to assemble the microneedles and the sensing chipsmanually. It is a more scalable manufacturing solution and may lowermanufacturing costs. The increased integration further makes it possibleto construct a biomarker monitoring and drug delivery feedback system.When providing therapy to a patient, such a feedback system may preventdelivery of too much drug which could become toxic to the patient. Thefeedback system is a closed-loop feedback system where the drug deliveryis dependent on the biomarker levels. A large number of biosensors maybe employed as an array for each microfluidic chamber of the capstructure served by microneedle(s). This provides better statisticalanalysis of the sensing results and reduces the signal to noise ratio(SNR) of the results. In accordance with some embodiments, the biosensorsystem package may be connected to a separate chip/die through wirebonding. In accordance with some embodiments, the biosensor systempackage may be connected to a separate chip/die through athrough-substrate via (TSV) structure.

FIG. 1A is a block diagram of an example biosensor system 100 inaccordance with some embodiments. FIG. 1B is a schematic diagram of anexample biosensor 103 used in the biosensor system 100 of FIG. 1A inaccordance with some embodiments. As shown in FIG. 1A, the examplebiosensor system 100 may include, among other things, a biosensor array102, a control sensor array 104, temperature sensors 106, a referenceelectrode 108, a sensor interface 130, an amplifier 132, a powerregulator 134, an analog-to-digital converter (ADC) 136, a digitalcontrol module 138, a wireless transceiver (TRX) 140, a heater 142, andbonding pads 144.

The biosensor array 102 may have at least one sensing element fordetecting a biological or chemical analyte. The biosensor array 102 mayinclude an array of biosensors (e.g., a biosensor 103 shown in FIG. 1B),where one or more of the biosensors in the array are functionalized todetect a particular target analyte. Different ones of the biosensors maybe functionalized using different capture reagents for detectingdifferent target analytes. The biosensors may be arranged in a pluralityof rows and columns, forming a 2-dimensional array of biosensors. Insome embodiments, each row of biosensors is functionalized using adifferent capture reagent. In some embodiments, each column ofbiosensors is functionalized using a different capture reagent. In someembodiments, a certain range of rows and columns of biosensors arefunctionalized using a different capture reagent. Further detailsregarding an example biosensor 103 is provided below with reference toFIG. 1B.

The control sensor array 104 has similar structures with the biosensorarray 102. The control sensor array 104 provides reference signals to becompared with the signals generated at the biosensor array 102, togenerate differential signals. The sensor interface 130 interfaces withthe biosensor array 102 and the control sensor array 104. The resultantdifferential signals are further amplified by the amplifier 132. Thereference electrode 108 provides a reference potential. The referenceelectrode 108 may be made of one of the following materials: Ag/AgCl,Cu/CuSO₄, AgCl, Au, and P. For Ag/AgCl, a chemical treatment may berequired on the deposited and patterned Ag layer to create the AgCl. ForCu/CuSO₄, a chemical treatment may be required on the deposited andpatterned Cu layer to create the CuSO₄. For applications where thesensing has to be done at certain temperatures, the heater 142 canadjust the temperature of the biosensor array 102 and the control sensorarray 104 based on feedback signals detected by the temperature sensors106. The ADC 136 may convert analog signals amplified by the amplifierto digital signals. The digital control module 138 may act as acontroller for the biosensor system 100. The bonding pads 144 are usedfor bonding the biosensor system to other chips or printed circuit board(PCB). Alternatively, the wireless transceiver 140 may transmit andreceive data via wireless communication.

As shown in FIG. 1B, the example biosensor 103 may include, among otherthings, a fluid gate 112, a source region 114, a drain region 116, asensing film 118, a channel region 120. A fluid 122 is over the sensingfilm 118. The fluid 122 may contain analyte not shown. The sensing film118 may be an electrically and chemically insulating layer thatseparates the fluid 122 from the channel region 120. The sensing film118 may include, among other things, a layer of a capture reagent. Thecapture reagent is specific to an analyte and capable of binding thetarget analyte or target reagent. Upon binding of the analyte, changesin the electrostatic potential at the surface of the sensing film 118occur, which in turn results in an electrostatic gating effect of thebiosensor 103, and a measurable change in a current I_(ds) 126 betweenthe source and drain electrodes. A voltage applied to the fluid gate 112may also change the I_(ds) 126.

FIG. 2A is a cross-sectional diagram illustrating a biosensor systempackage 200 a in accordance with some embodiments. FIG. 2B is across-sectional diagram illustrating another biosensor system package200 b in accordance with some embodiments. FIG. 6A and FIG. 6B areflowcharts illustrating a method of fabricating the biosensor systempackage 200 a and 200 b (collectively 200) of FIG. 2A and FIG. 2B,respectively, in accordance with some embodiments. FIG. 6C is aflowchart illustrating the step 624 of the method 600 in accordance withsome embodiments. FIG. 6D is a flowchart illustrating the step 636 ofthe method 600 in accordance with some embodiments. FIG. 6E is anotherflowchart illustrating the step 636 of the method 600 in accordance withsome embodiments. It should be noted that additional steps can beprovided before, during, and after the method 600, and some of the stepsdescribed below can be replaced or eliminated, for additionalembodiments of the method. Further, it should be noted that the method600 is a CMOS-compatible process flow. FIGS. 7-38 are cross-sectionaldiagrams illustrating the biosensor system package constructed accordingto one or more steps of the method of FIG. 6A and FIG. 6B in accordancewith some embodiments. It should be noted that FIGS. 2A-2B and 7-38 areschematic and are not drawn to scale.

As shown in FIGS. 2A and 2B, each of the biosensor system package 200 aand 200 b (collectively 200) has a front side (F) and a back side (B).In the example shown in FIG. 2A and FIG. 2B, each of the biosensorsystem package 200 a and 200 b includes, among other things, a buriedoxide (BOX) layer 206, a semiconductor layer 208, a transistor structure(i.e., a FET) 210, a temperature sensor 211, a multilevel-interconnect(MLI) structure 212, a carrier substrate 220, a separate chip/die (e.g.,a RAM and data processing chip) 250, a trench 222, an interface layer(e.g., a high-k material layer) 224, a reference electrode 227, and acap structure 228. The separate chip 250 is connected to the biosensorsystem package 200 a of FIG. 2A by wire bonding, while the separate chip250 is connected to the biosensor system package 200 b of FIG. 2B by athrough-substrate via (TSV) structure 246 and a solder bump 248. The TSVstructure 246 is at the front side (F). The cap structure 228 isattached to the back side (B). The cap structure 228 includes, amongother things, a cap structure substrate 230, chamber(s) 244, amicroneedle 241, an inlet 274, and optionally a high-k dielectricmaterial layer 242. The chamber 244 can accommodate fluid samples to betested. Details of the components of the biosensor system package 200will be described below with reference to FIGS. 6A-6E and 7-38 .

FIG. 3A is a top view of an integrated continuous biomarker monitoringand treatment chip 300 in accordance with some embodiments. FIG. 3B is across-sectional diagram illustrating the cross section of the integratedcontinuous biomarker monitoring and treatment chip 300 along a line A-A′of FIG. 3A in accordance with some embodiments. FIG. 3C is across-sectional diagram illustrating the cross section of the integratedcontinuous biomarker monitoring and treatment chip 300 along a line B-B′of FIG. 3A in accordance with some embodiments. FIG. 3D is across-sectional diagram illustrating the cross section of the integratedcontinuous biomarker monitoring and treatment chip 300 along a line C-C′of FIG. 3A in accordance with some embodiments. FIG. 3E is a diagramillustrating the use of the integrated continuous biomarker monitoringand treatment chip 300 of FIG. 3A in accordance with some embodiments.FIG. 3F is a flowchart illustrating a method 390 of operating theintegrated continuous biomarker monitoring and treatment chip 300 ofFIG. 3A in accordance with some embodiments.

As shown in FIGS. 3A-3D, the integrated continuous biomarker monitoringand treatment chip 300 may include, among other things, a complementarymetal-oxide-semiconductor (CMOS) application-specific integrated circuit(ASIC) 348, a cap structure 362 attached to the back side of the CMOSASIC 348, and a gas-liquid separation membrane 358. In the example shownin FIGS. 3A-3D, the cap structure 362 is attached to the CMOS ASIC 348via wafer bonding structures 364, though other means of bonding may beemployed. The example CMOS ASIC 348 has, among other things, a biosensorarray 302 and a control sensor array 304 at the back side of the CMOSASIC 348. The example cap structure 362 has, among other things, a fluidchamber 354 and multiple microneedles 350. The fluid chamber 354 mayaccommodate fluid which may contain biomarker molecules (e.g., glucosemolecules) 360. The biosensor array 302 and the control sensor array 304may detect the existence and density of the biomarker molecules 360 asexplained above. The fluid enters the fluid chamber 354 via the multiplemicroneedles 350. The number of microneedles 350 may vary as needed. Foreach microneedle 350, there is a (silicon) microneedle channel 352 thatconnects the fluid chamber 354 with outside. The gas-liquid separationmembrane 358 is configured to eliminate air bubbles in the fluid chamber354 since only gas can pass the gas-liquid separation membrane 358.

Referring to FIGS. 3E and 3F, the integrated continuous biomarkermonitoring and treatment chip 300 is used for continuous biomarkermonitoring, and the method 390 of operating the integrated continuousbiomarker monitoring and treatment chip 300 starts at step 391. At step391, the microneedles 350 are inserted into a skin 368. Specifically,the microneedles 350 penetrate the skin 368 of a body (e.g., human body)366. Biomarker molecules (e.g., glucose molecules) 360 may exist in thebody 366 (beneath the skin 368, inside and around the blood vessel 370).At step 392, interstitial fluid may naturally flow into the fluidchamber 354 via the microneedle channels 352 of the microneedles 350 dueto pressure. As a result, the biomarker molecules 360 enter the fluidchamber 354 as well. At step 393, the CMOS ASIC 348 with the biosensorarray 302 and the control sensor array 304 continuously senses thebiomarker molecules 360 and transmits data. Specifically, the biosensorarray 302, along with the control sensor array 304, may detect theexistence and density of the biomarker molecules 360. The detectedsignal is further processed (e.g., amplified, converted, etc.) by theCMOS ASIC 348. The result data may be transmitted via either the bondingpads 344 shown in FIG. 3A or alternatively the wireless transceivermodule 140 shown in FIG. 1A. As such, the integrated continuousbiomarker monitoring and treatment chip 300 may continuously sense thebiomarker molecules 360, which in turn may be used for diagnose ortreatment of certain diseases (e.g., diabetes) related to the biomarkermolecules 360.

FIG. 4A is a top view of a simultaneously biomarker monitoring and drugreleasing treatment chip 400 and the application thereof in accordancewith some embodiments. FIG. 4B is a flowchart illustrating a method 490for simultaneous biomarker monitoring and drug releasing treatment chip400 of FIG. 4A in accordance with some embodiments.

As shown in FIG. 4A, the simultaneously biomarker monitoring and drugreleasing treatment chip 400 may include, among other things, a CMOSASIC 448, a cap structure 462 attached to the back of the CMOS ASIC 448,and two gas-liquid separation membranes 458 a and 458 b. In the exampleshown in FIG. 4A, the cap structure 462 is attached to the CMOS ASIC 448via wafer bonding structures not shown, though other means of bondingmay be employed. The example CMOS ASIC 448 has, among other things, abiosensor array 402 and a control sensor array 404 at the back of theCMOS ASIC 448. The example cap structure 462 has, among other things, afluid chamber 454, a drug channel 455, and multiple microneedles 450.The fluid chamber 454 may accommodate fluid which may contain biomarkermolecules (e.g., glucose molecules) not shown. The biosensor array 402and the control sensor array 404 may detect the existence and density ofthe biomarker molecules as explained above. The fluid enters the fluidchamber 454 via the multiple microneedles 450. The number ofmicroneedles 450 may vary as needed. On the other hand, the drug channelmay accommodate drug solution 474 which is originally outside thesimultaneously biomarker monitoring and drug releasing treatment chip400. The drug solution 474, outside the simultaneously biomarkermonitoring and drug releasing treatment chip 400, is connected to thedrug channel 455 through a fluidics valve 476 and a pump 472. Thefluidics valve 476 can be turned on and off based on control signals.When the fluidics valve 476 is turned on, the drug solution 474 can bepumped into the drug channel 455 for delivery via the microneedles 450.The gas-liquid separation membranes 458 a and 458 b are configured toeliminate air bubbles in the fluid chamber 454 and the drug channel 455,respectively.

Referring to FIG. 4B and FIG. 4A, the simultaneously biomarkermonitoring and drug releasing treatment chip 400 is used forsimultaneously biomarker monitoring and drug releasing treatment, andthe method 490 for simultaneous biomarker monitoring and drug releasingtreatment chip starts at step 491. At step 491, the microneedles 450 areinserted into a skin not shown. Specifically, the microneedles 450penetrate the skin of a body (e.g., human body) not shown. Biomarkermolecules (e.g., glucose molecules) not shown may exist in the body.Interstitial fluid not shown may naturally flow into the fluid chamber454 via the microneedles 450 due to pressure. As a result, the biomarkermolecules not shown may enter the fluid chamber 454 as well. At step492, the fluidics valve 476 is turned off. As such, the drug solution474 cannot flow into the drug channel 455. At step 493, the CMOS ASIC448 with the biosensor array 402 and the control sensor array 404continuously senses the biomarker molecules and transmits data.Specifically, the biosensor array 402, along with the control sensorarray 404, may detect the existence and density of the biomarkermolecules. The detected signal is further processed (e.g., amplified,converted, etc.) by the CMOS ASIC 448. At step 494, the CMOS ASIC 448determines that the biomarker concentration reaches an abnormal value(e.g., above a threshold concentration). Then at step 495, the fluidicsvalve 476 is turned on. As a result, at step 496, the drug solution 474flows into the drug channel 455 (e.g., pumped by the pump 472) andsubsequently flows into the skin/body through the microneedles 450. Assuch, the drug solution 474 is delivered and the drug releasingtreatment begins. On the other hand, the CMOS ASIC 448 stillcontinuously senses the biomarker molecules and transmits data as atstep 493. Due to the drug releasing treatment, the biomarkerconcentration becomes lower over time. At step 497, the CMOS ASIC 448determines that the biomarker concentration turns normal (e.g., belowthe threshold concentration) again. As a result, the fluidics valve 476is turned off again such that the drug solution 474 cannot flow into thedrug channel 455. Accordingly, the method 490 can achieve simultaneousbiomarker monitoring and drug releasing treatment with one integratedchip. In other words, the biomarker concentration is being constantlymonitored and the drug releasing treatment is triggered automaticallybased on the real-time biomarker concentration.

FIG. 5A is a top view of another integrated continuous biomarkermonitoring and treatment chip 500 in accordance with some embodiments.FIG. 5B is a cross-sectional diagram illustrating the cross section ofthe integrated continuous biomarker monitoring and treatment chip 500along a line A-A′ of FIG. 5A in accordance with some embodiments. FIG.5C is a cross-sectional diagram illustrating the cross section of theintegrated continuous biomarker monitoring and treatment chip 500 alonga line B-B′ of FIG. 5A in accordance with some embodiments. FIG. 5D is across-sectional diagram illustrating the cross section of the integratedcontinuous biomarker monitoring and treatment chip 500 along a line C-C′of FIG. 5A in accordance with some embodiments. FIG. 5E is a diagramillustrating the use of the integrated continuous biomarker monitoringand treatment chip 500 of FIG. 5A in accordance with some embodiments.FIG. 5F is a flowchart illustrating a method 580 for continuousbiomarker monitoring in accordance with some embodiments. FIG. 5G is adiagram illustrating the use of the integrated continuous biomarkermonitoring and treatment chip 500 of FIG. 5A in accordance with someembodiments. FIG. 5H is a flowchart illustrating a method 590 forcontinuous biomarker monitoring with closed-loop drug releasingtreatment in accordance with some embodiments.

As shown in FIGS. 5A-5D, the integrated continuous biomarker monitoringand treatment chip 500 may include, among other things, a CMOS ASIC 548,a cap structure 562 attached to the back of the CMOS ASIC 548, an inlet578, and a gas-liquid separation membrane 558. In the example shown inFIGS. 5A-5D, the cap structure 562 is attached to the CMOS ASIC 548 viawafer bonding structures 564, though other means of bonding may beemployed. The example CMOS ASIC 548 has, among other things, a biosensorarray 502 and a control sensor array 504 at the back of the CMOS ASIC548. The example cap structure 562 has, among other things, a fluidchamber 554 and multiple microneedles 550. The fluid chamber 554 mayaccommodate fluid which may contain biomarker molecules (e.g., glucosemolecules) 560. The biosensor array 502 and the control sensor array 504may detect the existence and density of the biomarker molecules 560 asexplained above. The fluid may enter the fluid chamber 554 via the inlet578 and/or the multiple microneedles 550. The number of microneedles 550may vary as needed. For each microneedle 550, there is a (silicon)microneedle channel 552 that connects the fluid chamber 554 withoutside. The gas-liquid separation membrane 558 is configured toeliminate air bubbles in the fluid chamber 554 since only gas can passthe gas-liquid separation membrane 558.

Referring to FIGS. 5E and 5F, the integrated continuous biomarkermonitoring and treatment chip 500 is used for continuous biomarkermonitoring. As shown in FIG. 5E, the fluid chamber 554 is connected tobuffer solution 575 through a fluidics valve 576 and a pump 572. Abuffer solution is an aqueous solution consisting of a mixture of a weakacid and its conjugate base, or vice versa. In one example, the buffersolution 575 is 1×PBS (1× Physiological Saline Solution) or PBS withlower concentrations such as 0.1×PBS or 0.01×PBS. In another example,the buffer solution 575 is HEPES[(4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid)]. In yet anotherexample, the buffer solution 575 is TRIS [tris(hydroxymethyl)aminomethane]. At step 581, the fluidics valve 576 is turned on and thebuffer solution 575 is filled in the fluid chamber 554. At step 582, themicroneedles 550 are inserted into a skin 568. Specifically, themicroneedles 550 penetrate the skin 568 of a body (e.g., human body)566. Biomarker molecules (e.g., glucose molecules) 560 may exist in thebody 566 (beneath the skin 568, inside and around the blood vessel 570).Interstitial fluid may naturally flow into the fluid chamber 554 via themicroneedle channels 552 of the microneedles 550 due to pressure. As aresult, the biomarker molecules 560 enter the fluid chamber 554 as well.At step 583, the fluidics valve 576 is turned off. At step 584, the CMOSASIC 548 with the biosensor array 502 and the control sensor array 504continuously senses the biomarker molecules 560 and transmits data.Specifically, the biosensor array 502, along with the control sensorarray 504, may detect the existence and density of the biomarkermolecules 560. The detected signal is further processed (e.g.,amplified, converted, etc.) by the CMOS ASIC 548. The result data may betransmitted via either the bonding pads 544 shown in FIG. 5A oralternatively the wireless transceiver module 140 shown in FIG. 1A. Assuch, the integrated continuous biomarker monitoring and treatment chip500 may continuously sense the biomarker molecules 560, which in turnmay be used for diagnose or treatment of certain diseases (e.g.,diabetes) related to the biomarker molecules 560.

On the other hand, referring to FIGS. 5G and 5H, the integratedcontinuous biomarker monitoring and treatment chip 500 is used forcontinuous biomarker monitoring with closed-loop drug releasingtreatment. As shown in FIG. 5G, the fluid chamber 554 is connected to apump 572 via the inlet 578, which is further connected to both buffersolution 575 and drug solution 574 through a fluidics valve 576 a (“V1”)and another fluidics valve 576 b (“V2”), respectively. At step 591, thefluidics valve 576 a is turned on and the fluidics valve 576 b is turnedoff. As a result, the buffer solution 575 is filled into the fluidchamber 554. At step 592, the microneedles 550 are inserted into a skin568. Specifically, the microneedles 550 penetrate the skin 568 of a body(e.g., human body) 566. Biomarker molecules (e.g., glucose molecules)560 may exist in the body 566 (beneath the skin 568, inside and aroundthe blood vessel 570). Interstitial fluid may naturally flow into thefluid chamber 554 via the microneedle channels 552 of the microneedles550 due to pressure. As a result, the biomarker molecules 560 enter thefluid chamber 554 as well. At step 593, both the fluidics valve 576 aand the fluidics valve 576 b are turned off. At step 594, the CMOS ASIC548 with the biosensor array 502 and the control sensor array 504continuously senses the biomarker molecules 560 and transmits data.Specifically, the biosensor array 502, along with the control sensorarray 504, may detect the existence and density of the biomarkermolecules 560. The detected signal is further processed (e.g.,amplified, converted, etc.) by the CMOS ASIC 548. The result data may betransmitted via either the bonding pads 544 shown in FIG. 5A oralternatively the wireless transceiver module 140 shown in FIG. 1A. Atstep 595, the CMOS ASIC 548 determines that the biomarker concentrationreaches an abnormal value (e.g., above a threshold concentration). Thenat step 596, the fluidics valve 576 b is turned on and the fluidicsvalve 576 a keeps off for a certain period of time. As a result, at step597, the drug solution 574 flows into the drug channel fluid chamber 554(e.g., pumped by the pump 572) and subsequently flows into the skin/bodythrough the microneedles 550. As such, the drug solution 474 isdelivered and the drug releasing treatment begins. On the other hand,the CMOS ASIC 448 still continuously senses the biomarker molecules andtransmits data as at step 594. Due to the drug releasing treatment, thebiomarker concentration becomes lower over time. After the certainperiod of time, at step 598, the fluidics valve 576 b is turned offwhile the fluidics valve 576 a is turned on. As a result, the buffersolution 575 can flow into the fluid chamber 554. Then at step 599, boththe fluidics valve 576 a and the fluidics valve 576 b are turned off.The method 590 then loops back to step 594. Accordingly, the method 590can achieve simultaneous biomarker monitoring with closed-loop drugreleasing treatment. In other words, the biomarker concentration isbeing constantly monitored and the drug releasing treatment is triggeredautomatically based on the real-time biomarker concentration. The buffersolution 575 is added to the fluid chamber 554 every time the drugsolution 574 is delivered.

As mentioned above, the biosensor system package 200 a of FIG. 2A andthe biosensor system package 200 b of FIG. 2B are fabricated by themethod 600 of FIGS. 6A-6B.

The method 600 begins at step 602 where a substrate is provided. Thesubstrate may be a semiconductor substrate (e.g., wafer). Thesemiconductor substrate may be a silicon substrate. Alternatively, thesubstrate may comprise another elementary semiconductor, such asgermanium; a compound semiconductor including silicon carbide, galliumarsenic, gallium phosphide, indium phosphide, indium arsenide, and/orindium antimonide; an alloy semiconductor including SiGe, GaAsP, AlInAs,AlGaAs, GaInAs, GaInP, and/or GaInAsP; or combinations thereof. Inembodiments shown in FIGS. 6A-6E and FIGS. 7-38 , the substrate is asemiconductor on insulator (SOI) substrate 202. The SOI substrate 202shown in FIG. 7 includes a bulk silicon layer 204, a buried oxide (BOX)layer 206, and a semiconductor layer 208 (i.e., an active layer 208).The buried oxide layer 206 may be formed by a process such as separationby implanted oxygen (SIMOX), and/or other suitable processes. Thesemiconductor layer 208 may include doped regions, such as p-wells andn-wells.

The method then proceeds to step 604 where a transistor structure and atemperature sensor are formed on the substrate. The transistor structure(i.e., the FET) may include a gate structure, a source region, a drainregion, and a channel region interposing the source and drain regions.It should be noted that in some embodiments, the transistor structure(i.e., the FET) may be an array of transistor structures. Forsimplicity, only one transistor structure is used as an example in thedescription below. As shown in the example in FIG. 7 , the source,drain, and/or channel region of the FET 210 may be formed on an activeregion in the semiconductor layer 208. The FET 210 may be an n-type FET(nFET) or a p-type FET (pFET). For example, the source/drain regions maycomprise n-type dopants or p-type dopants depending on the FETconfiguration. The gate structure may include a gate dielectric layer, agate electrode layer, and/or other suitable layers. In an embodiment,the gate electrode is polysilicon. Other exemplary gate electrodesinclude metal gate electrodes including material such as, Cu, W, Ti, Ta,Cr, Pt, Ag, Au; suitable metallic compounds like TiN, TaN, NiSi, CoSi;combinations thereof; and/or other suitable conductive materials. In anembodiment, the gate dielectric is silicon oxide. Other exemplary gatedielectrics include silicon nitride, silicon oxynitride, a dielectricwith a high dielectric constant (high-k), and/or combinations thereof.Examples of high-k materials include hafnium silicate, hafnium oxide,zirconium oxide, aluminum oxide, tantalum pentoxide, hafniumdioxide-alumina (HfO₂—Al₂O₃) alloy, or combinations thereof. The FET 210may be formed using typical CMOS processes such as, photolithography;ion implantation; diffusion; deposition including physical vapordeposition (PVD), metal evaporation or sputtering, chemical vapordeposition (CVD), plasma-enhanced chemical vapor deposition (PECVD),atmospheric pressure chemical vapor deposition (APCVD), low-pressure CVD(LPCVD), high density plasma CVD (HDPCVD), atomic layer deposition(ALD), spin on coating; etching including wet etching, dry etching, andplasma etching; and/or other suitable CMOS processes.

The temperature sensor may detect the temperature of the chamber 244 inFIGS. 2A and 2B. As shown in the example in FIG. 7 , the temperaturesensor 211 is formed in the semiconductor layer 208. In someembodiments, the temperature sensor 211 may include a thermal couplingelement (e.g., a platinum thermocouple).

The method 600 then proceeds to step 606 where a multi-layerinterconnect (MLI) structure is formed above the transistor structure.The MLI structure may include conductive lines, conductive verticalinterconnect accesses (vias), and/or interposing dielectric layers(e.g., interlayer dielectric (ILD) layers). The MLI structure mayprovide physical and electrical connection to the transistor (i.e., theFET), described above with reference to step 604. The conductive linesmay comprise copper, aluminum, tungsten, tantalum, titanium, nickel,cobalt, metal silicide, metal nitride, poly silicon, combinationsthereof, and/or other materials possibly including one or more layers orlinings. The interposing dielectric layers (e.g., ILD layers) maycomprise silicon dioxide, fluorinated silicon glass (FGS), SILK (aproduct of Dow Chemical of Michigan), BLACK DIAMOND (a product ofApplied Materials of Santa Clara, Calif.), and/or other suitableinsulating materials. The MLI structure may be formed by suitableprocesses typical in CMOS fabrication such as CVD, PVD, ALD, plating,spin-on coating, and/or other processes.

As shown in the example in FIG. 7 , an MLI structure 212 is disposed onthe substrate 202 and above the FET 210 and the temperature sensor 211.The MLI structure 212 includes a plurality of conductive lines 214connected by conductive vias or plugs 216. In one embodiment, theconductive lines 214 include aluminum and/or copper. In one embodiment,the vias or plugs 216 include tungsten. In another embodiment, the viasor plugs 216 include copper. In one embodiment, the interposingdielectric layers 218 are disposed on the substrate 202 includinginterposing the conductive features of the MLI structure 212. Theinterposing dielectric layers 218 may be ILD layers. In anotherembodiment, the dielectric layer 218 is a single ILD layer. In oneembodiment, each of the interposing dielectric layer 218 includessilicon oxide. The MLI structure 212 may provide electrical connectionto the gate and/or the source/drain of the FET 210. As shown in theexample in FIG. 7 , the MLI structure 212 is at the front side (F) whilethe substrate 202 is at the back side (B).

Additionally, conductive line(s) in the first metal layer (“M1 layer”)may be used as the heater 142 as shown in FIG. 1A. In other words,conductive line(s) can be an embedded (electric-resistive) heater usedto generate heat. In some embodiments, the heater may have multiplezones that are individually controllable, and/or is made of materialssuch as Al, Cu, TiAlN, though other material may also be employed.Alternatively, the heater maybe arranged under a semiconductor substrateand made of silicon or polysilicon. By using an embedded heater,temperature control and uniformity may be improved.

The method 600 then proceeds to step 608 where a carrier substrate isattached to the front side (F). In other words, the carrier substrate isattached to the MLI structure. The carrier substrate may protect thefront side (F) during subsequent steps. In one embodiment, the carriersubstrate is bonded to the MLI structure. In another embodiment, thecarrier substrate is bonded to a passivation layer formed on the MLIstructure. The carrier substrate may be attached using fusion,diffusion, eutectic, and/or other suitable bonding methods. Exemplarycompositions for the carrier substrate include silicon, glass, andquartz. It should be noted that other compositions are possible andwithin the scope of the present disclosure. As shown in the example inFIG. 8 , a carrier substrate 220 is attached to the MLI structure 212.In some embodiments, the carrier substrate 220 may includefunctionalities such as, interconnect features, wafer bonding sites,defined cavities, and/or other suitable features.

The method 600 then proceeds to step 610 where the wafer is flipped. Asshown in FIG. 9 , the back side (B) is on the top. In other words, thebulk silicon layer 204 is on the top. The method 600 then proceeds tostep 612 where the bulk silicon layer 204 is removed. The removal may beaccomplished by mechanical or chemical means. For example, a mechanicalmeans includes polishing or grinding, such as chemical mechanicalpolishing (CMP). A chemical means includes wet etch, such asHF/nitric/acetic acid (HNA) or tetramethylammonium hydroxide (TMAH) ordry etch including plasma and non-plasma etch. As shown in the examplein FIG. 10 , the bulk silicon layer 204 in FIG. 9 is removed. The buriedoxide layer 206 is on the top at the back side (B).

The method 600 then proceeds to step 614 where the buried oxide layer ispatterned to form an opening at the back side (B). A photoresist patternis formed on the buried oxide layer. In some embodiments, thephotoresist pattern protects some of the buried oxide layer from asubsequent non-plasma etch to expose the backside (B) of the biosensorsystem package. Specifically, the photoresist pattern protects some ofthe buried oxide layer from the subsequent non-plasma etch to expose theactive region of the transistor structure formed at step 604. Thenon-plasma etch may be a wet etch or a dry etch that does not involveplasma. In some embodiments, a two-step etch process may be employed toform the opening at the back side (B). The first etching step containsplasma and the second etching step is a non-plasma etch. As shown in theexample in FIG. 11 , the non-plasma etch forms a trench 222 having abottom exposing the channel region of the FET 210. A non-plasma etch isused to avoid plasma-induced damage (PID) at the exposed surface of thechannel region 219. In a non-limiting example, the height of the trench222 may range between 0.3 μm to 1 μm, while the width of the trench 222may range between 0.5 μm to 200 μm (in some extreme cases). In someembodiments, the sidewall profile of the trench 222 is substantiallystraight. After the non-plasma etch, the photoresist pattern is removed.A PID-less photoresist removal process such as stripping and ozoneashing may be used. Because the exposed surface of the trench 222 andthe exposed surface of the channel region of the FET 210 are susceptibleto plasma-induced damage (PID), some plasma ashing processes may not beused to remove the photoresist pattern.

The method 600 then proceeds to step 616. At step 616, an interfacelayer is deposited. In one embodiment, the interface layer is a high-kmaterial layer. The interface layer is compatible (e.g., friendly) forbiomolecules or bio-entities binding. For example, the interface layermay include a capture reagent layer, which is a layer of capture reagentcapable of binding a target analyte in the fluid samples. In someembodiments, the interface layer includes a plurality of layers. Forinstance, the interface layer may include a dielectric material (e.g., ahigh-k material), a conductive material, and/or other suitable materialfor holding a receptor. Exemplary interface materials include high-kdielectric films, metals, metal oxides, dielectrics, and/or othersuitable materials. As a further example, exemplary interface layermaterials include HfO₂, Ta₂O₅, Pt, Au, W, Ti, Al, Cu, oxides of suchmetals, SiO₂, Si₃N₄, Al₂O₃, TiO₂, TiN, ZrO₂, SnO, SnO₂; and/or othersuitable materials. The interface layer may be formed using CMOSprocesses such as, for example, physical vapor deposition (PVD)(sputtering), chemical vapor deposition (CVD), plasma-enhanced chemicalvapor deposition (PECVD), atmospheric pressure chemical vapor deposition(APCVD), low-pressure CVD (LPCVD), high density plasma CVD (HDPCVD), oratomic layer CVD (ALCVD). A photoresist pattern is formed over theinterface layer to protect a portion of the interface layer. The portionover the channel region of the FET is protected. Unprotected portions ofthe interface layer are removed in a subsequent etch process. The etchprocess may involve any known etch process including plasma etch, sincethe portion susceptible to PID is protected. The interface layercompletely covers the channel region and may partially cover the sourceregion and drain region. The partial coverage of the source and drainregion may be adjusted based on the FET design and area requirements forthe interface layer. In some embodiments, the interface layer may not bepatterned and etched and remains over the respective surfaces of theFET.

As shown in the example in FIG. 11 , an interface layer 224 (e.g., ahigh-k material layer) is formed on the exposed surface of the trench222 and the exposed surface of the active region 219 of the FET 210.Additionally, the interface layer 224 is deposited over the entiresurface of the buried oxide layer 206.

Alternatively at step 618, an interface layer is deposited while somebonding sites are exposed. The boding sites are used for bonding amicrofluidic channel cap structure to the back side (B), which will bedescribed in detail below at step 626. It should be noted that whetherbonding sites are required depends on specific bonding requirements.Similar to step 616, the interface layer may be formed using CMOSprocesses such as, for example, PVD (sputtering), CVD, PECVD, APCVD,LPCVD, HDPCVD, or ALCVD. A photoresist pattern is formed over theinterface layer to protect a portion of the interface layer, and thebonding sites are not protected. Unprotected portions of the interfacelayer are removed in a subsequent etch process. The etch process mayinvolve any known etch process including plasma etch, since the portionsusceptible to PID is protected. After etching and optionally adding apassivating or blocking agent, the photoresist is removed in a PID-freephotoresist removal process.

As shown in the example in FIG. 12 , the interface layer 224 (e.g., ahigh-k material layer) is formed on the exposed surface of the trench222 and the exposed surface of the active region 219 of the FET 210,while two bonding sites 226 are exposed. In other words, the buriedoxide layer 206, except for the two bonding sites 226, are covered bythe interface layer 224. It should be noted that the shape of thebonding sites may vary depending on the shape of the microfluidicchannel cap structure.

The method 600 then proceeds to step 620. At step 620, the buried oxidelayer, the semiconductor layer, and the first interposing dielectriclayer are patterned and etched to form opening(s) at the back side (B)to expose conductive line(s) at the first metal layer (“M1 layer”). Aphotoresist pattern is formed on the buried oxide layer and theinterface layer deposited at step 616 or 618. Similar to step 614, thephotoresist pattern protects the interface layer and some of the buriedoxide layer from a subsequent etch to expose the backside (B) of thebiosensor system package in some embodiments. As shown in the example inFIG. 13 , two openings 225 a and 225 b (collectively 225) are formed atthe back side (B). The number of openings 225 may vary as needed. In theexample shown in FIG. 13 , the opening 225 a is used for depositing areference electrode while the opening 225 b is used for subsequent wirebonding. In another example, there is only one opening 225 used fordepositing a reference electrode. In other words, no opening 225 isformed for wire bonding. As shown in FIG. 13 , the openings 225 a and225 b are formed in the buried oxide layer 206, the semiconductor layer208, and the first interposing dielectric layer 218-1, and have bottomsexposing the conductive lines 214 a and 214 b, respectively, at the M1layer. In some embodiments, the sidewall profile of the trench 222 issubstantially straight. After the etch process, the photoresist patternis removed.

The method 600 then proceeds to step 622. At step 622, a referenceelectrode is deposited in one of the opening(s). As a result, thereference electrode is connected to one conductive line exposed in theopening at step 620. As mentioned above, the reference electrode may bemade of one of the following materials: Ag/AgCl, Cu/CuSO₄, AgCl, Au, andP. For Ag/AgCl, a chemical treatment may be required on the depositedand patterned Ag layer to create the AgCl. For Cu/CuSO₄, a chemicaltreatment may be required on the deposited and patterned Cu layer tocreate the CuSO₄. As shown in FIG. 14 , the reference electrode 227 isdeposited in the opening 225 a formed at step 620. The electrode 227 isconnected to the conductive line 214 a exposed in the opening 225 a.

The method 600 then proceeds to step 624. At step 624, a cap structureis fabricated. FIG. 6C is a flowchart diagram illustrating the step 624of the method 600 of FIG. 6B in accordance with some embodiments. Thestep 624 is a CMOS-compatible process flow. At step 652, a cap structuresubstrate is provided. The cap structure substrate may be a siliconsubstrate, though other suitable materials may be employed. As shown inthe example in FIG. 15 , a silicon substrate 230 is provided.

At step 654, the cap structure substrate is patterned and etched topredefine global cavity regions. The global cavity region corresponds tothe microfluidic channel. A photoresist pattern is formed on the capstructure substrate. The photoresist pattern protects some of the capstructure substrate from a subsequent etch to predefine the globalcavity region. After patterning the cap structure substrate, the globalcavity regions are predefined by etching the cap structure substrate.The etching process may be a wet etch, such as HF/nitric/acetic acid(HNA) or tetramethylammonium hydroxide (TMAH) or dry etch includingplasma and non-plasma etch. Afterwards, the photoresist is removed. Asshown in the example in FIG. 16 , two global cavity regions 232 arepredefined at the top surface of the cap structure substrate 230, andthe cap structure substrate 230 has been etched from 0.11 μm to 0.51 μmin this example.

At step 656, a hard mask is deposited on bonding areas of the capstructure substrate. In some embodiments, the bonding areas of the capstructure substrate correspond to the bonding sites on the buried oxidelayer at step 618. Specifically, the bonding areas of the cap structuresubstrate interface with the bonding sites on the buried oxide layer,and the cap structure is bonded to the buried oxide layer (or anyappropriate intermediate bonding layer deposited and patterned on theburied oxide layer), which will be described in detail below at step626. The hard mask can protect the bonding areas from subsequent etchingprocesses. In some embodiments, the hard mask may be formed of oxide. Insome embodiments, the hard mask may be formed of poly silicon. The hardmask is formed using suitable processes such as CVD and/or the like. Ina non-limiting example, the thickness of the hard mask ranges from 0.3μm to 1 μm. As shown in the example in FIG. 17 , the hard masks 236(e.g., oxide hard mask) are deposited on the bonding areas 234 of thecap structure substrate 230. The hard masks 236 may protect the bondingareas 234 from subsequent etching processes.

At step 658, certain regions of the global cavity regions are patternedand etched. A photoresist pattern is formed on the hard mask andportions of the global cavity regions. The photoresist pattern protectsthe hard mask and portions of the global cavity region from a subsequentetch. Subsequently, the cap structure substrate is etched. The etchingprocess may be a wet etch, such as HF/nitric/acetic acid (HNA) ortetramethylammonium hydroxide (TMAH) or dry etch including plasma andnon-plasma etch. Afterwards, the photoresist is removed. As shown in theexample in FIG. 18 , the photoresist pattern 238 is on the hard mask 236and portions of the global cavity regions 232. The exposed portions ofthe global cavity region 232 are etched to form deep regions 239. Thephotoresist pattern 238 is then removed, and the structure is as shownin the example in FIG. 19 . The entire global cavity regions 232,including the deep regions 239, are exposed, while the bonding areas 234are covered by the hard masks 236.

At step 660, the entire global cavity regions are blanket etched.Specifically, the entire global cavity regions, including the deepregions, are etched back evenly by a certain depth, to form the chambersof the cap structure. The chambers of the cap structure may be used aseither fluid chambers (e.g., the fluid chamber 454 as shown in FIG. 4A)or drug channels (e.g., the drug channel 455 as shown in FIG. 4A). Onthe other hand, the bonding areas covered by the hard masks areprotected during the blanket etch. The blanket etching process may beany suitable etching processes such as wet etch or dry etch includingplasma and non-plasma etch. As shown in the example in FIG. 20 , theentire global cavity regions 232 of the cap structure substrate 230,including the deep regions 239, are etched by a predefined etch depthED. The predefined etch depth ED corresponds to the desired height ofthe chambers 244 of the cap structure 228.

Optionally at step 662, a high-k dielectric material layer is depositedon the global cavity regions and the hard masks. Step 662 is optionaldepending on applications. The high-k dielectric material layer may beformed using CMOS processes such as, for example, PVD (sputtering), CVD,PECVD, APCVD, LPCVD, HDPCVD, or ALCVD. In one non-limiting example, thehigh-k dielectric material layer has a thickness of 2 nm to 3 nm. Asshown in the example in FIG. 21 , the high-k dielectric material layer242 is deposited on the global cavity regions 232 (thus the chambers244) and the hard masks 236. The high-k dielectric material layer 242covers the bottom and sidewalls of the chambers 244, the bottom andsidewalls of the deep regions 239, and the hard mask 236.

Optionally at step 664, the interface layer on the top of the hard maskis removed. In one embodiment, a photoresist spray coater may besprayed, by a spray coating process, to cover the global cavity region.The photoresist spray coater protects the high-k dielectric materiallayer when the high-k dielectric material layer on the hard mask isremoved. The interface layer on the top of the hard mask is removed bysuitable processes such as plasma etching. In an example plasma etchingprocess, a mixture of gasses comprising oxygen, a fluorine-containingmaterial and an inert gas is provided, and a high-speed stream of glowdischarge (plasma) of the mixture of gasses is shot (in pulses) at thehigh-k dielectric material layer. The spray coating process is used tocoat photoresist over a region with deep features. In the spray coatingprocess, fine droplets of photoresist are deposited onto the structure.The angle at which the photoresist droplets are sprayed permits thephotoresist to make its way into the deep trenches and sidewalls.

At step 666, the hard mask is removed. The hard mask is removed by anysuitable processes. In one embodiment, the hard mask is removed by wetetch. In some embodiments, the wet etch is a fluorine containing etch,such as dilute hydrofluoric acid (HF). In some embodiments, the wet etchis an ammonia hydroxide/hydrogen peroxide etch. The wet etch removes thehard mask without substantially removing or harming the high-kdielectric material layer. As shown in the example in FIG. 22 , theoptional high-k dielectric material layer 242 on the hard mask 236 andthe hard mask 236 are removed at step 664 and step 666, respectively.The bonding areas 234 are exposed. The bottom and sidewalls of theglobal cavity regions 232 and deep regions 239 are covered with thehigh-k dielectric material layer 242. As such, the cap structure 228 isfabricated.

Referring back to FIG. 6B, the method 600 proceeds to step 626 where thecap structure is bonded to the backside of the biosensor system package.Specifically, the cap structure is bonded to the buried oxide layer. Insome embodiments, the bonding sites of the buried oxide layer interfacewith the bonding areas of the cap structure substrate. In otherembodiments, an intermediate bonding layer, that is deposited andpatterned on the buried oxide layer, interfaces with the bonding areasof the cap structure substrate. The cap structure may be bonded to thebackside of the biosensor system package using fusion bond, eutecticbond, anodic bond, and/or other suitable bonding methods. Fusion bondingutilizes temperature and pressure to join semiconductor materials. Inone non-limiting example, in a room-temperature fusion bonding process,a bonder device forces the cap structure and the backside of thebiosensor system package together. This is followed by an annealingprocess to increase the bond strength. In a eutectic bond, anintermediate metal layer that can produce a eutectic system is utilized.The eutectic metals are alloys that transform directly from solid toliquid state, or vice versa from liquid to solid state, at a specificcomposition and temperature without passing a two-phase equilibrium. Asthe eutectic temperature can be much lower than the melting temperatureof the two or more pure elements, the eutectic bond may have thebenefits of low processing temperatures, low resultant stress induced infinal assembly, high bonding strength, large fabrication yield and agood reliability. In an anodic bond, glasses are sealed to eithersilicon or metal without introducing an intermediate layer.

As shown in the example in FIG. 23 , the cap structure 228 is bonded tothe backside (B) of the biosensor system package 200. Specifically, thecap structure 228 is bonded to the buried oxide layer 206. The bondingsites 226 of the buried oxide layer 206 interface with the boding areas234 of the cap structure substrate 230. In the example shown in FIG. 23, the conductive line 214 b, as mentioned above with reference to FIG.14 , may be used for wire bonding later.

Alternatively, as shown in the example in FIG. 24 , the cap structure228 is bonded to the backside (B) of the biosensor system package 200.Different from the example shown in FIG. 23 , a through-substrate via(TSV) structure rather than a wire bonding is used for connecting thebiosensor system package 200 with a separate chip later. The TSVstructure will be described in detail below.

For embodiments with TSV structures as mentioned above, the method 600then optionally proceeds to step 628 where the wafer is flipped.Afterwards, the carrier substrate which is at the front side (F) of thebiosensor system package is now on the top. The method 600 thenoptionally proceeds to step 630 where the carrier substrate is thinned.In one example, the carrier substrate is thinned by grinding. Thegrinding process may include rotating a disk holding the biosensorsystem package lined with an appropriate grinding material. It should benoted that other processes such as CMP may also be employed. As shown inFIG. 25 , the carrier substrate 220 has been thinned. The thickness ofthe carrier substrate is selected in accordance with step 632 which willbe discussed below.

The method 600 then optionally proceeds to step 632 where athrough-substrate via (TSV) structure is created through the carriersubstrate and connected to the MLI structure. The TSV is used to provideelectrical connections and for heat dissipation for the biosensor systempackage 200. As shown in the example in FIG. 26 , a TSV structure 246 iscreated through the carrier substrate 220 and connected to the MLIstructure 212. Although only one TSV structure 246 is shown in theexample in FIG. 26 , more than one TSV structure may be formed to passthrough the carrier substrate 220. The TSV structure 246 includes aliner 246 a, a diffusion barrier layer 246 b, and a conductive material246 c. In one embodiment, the TSV structure 246 is formed by thefollowing operations. Firstly, a TSV opening is formed extending to aconductive line 214 of the MLI structure 212 by one or more etchingprocesses. After the TSV opening is formed, the liner 246 a is formed onsidewalls of the TSV opening to act as an isolation layer, such that theconductive material 246 c of the TSV structure 246 and the carriersubstrate 220 do not directly contact with each other. Afterwards, thediffusion barrier layer 246 b is conformally formed on the liner 246 aand on the bottom of the TSV opening. The diffusion barrier layer 246 bis used to prevent the conductive material 246 c, which will be formedlater, from migrating to undesired regions. After the diffusion barrierlayer 246 b is formed, the conductive material 246 c is used to fillinto the TSV opening. Afterwards, excess liner 246 a, diffusion barrierlayer 246 b, and conductive material 246 c, which are on the outside ofthe TSV opening, are removed by a planarization process, such as achemical mechanical polishing (CMP) process, although any suitableremoval process may be used.

The liner 246 a is made of an insulating material, such as oxides ornitrides. The liner 246 a may be formed by using a PECVD process orother applicable processes. The liner 246 a may be a single layer ormulti-layers. In some non-limiting examples, the liner 246 a has athickness in a range from about 100 Å to about 5000 Å. The diffusionbarrier layer 246 b is made of Ta, TaN, Ti, TiN or CoW. In someembodiments, the diffusion barrier layer 246 b is formed by a PVDprocess. In some embodiments, the diffusion barrier layer 246 b isformed by plating. In some embodiments, the conductive material 246 c ismade of copper, copper alloy, aluminum, aluminum alloys, or combinationsthereof. Alternatively, other applicable materials may be used. Thewidth, depth, and aspect ratio of the TSV structure 246 may be selectedunder different circumstances. Since the carrier substrate 220 isthinned at step 630, the TSV structure 246 has a relatively small aspectratio. As such, the void problems and the extrusion or diffusionproblems resulting from a high aspect ratio of the TSV structure areresolved or greatly reduced. In addition, the overall package height ofthe biosensor system package 200 is reduced to meet advanced packagingrequirements. As such, the biosensor system package 200 may achieve asmall form factor.

The method 600 then proceeds to optional step 634 where the wafer isflipped for the case where a TSV structure was created. Afterwards, thecap structure is on the top, whereas the TSV structure is at the bottom.The method 600 then proceeds to step 636 where microneedle(s) arecreated at the back side (B) of the biosensor system package. FIG. 6D isa flowchart diagram illustrating the step 636 of the method 600 of FIG.6B in accordance with some embodiments. FIG. 6E is another flowchartdiagram illustrating the step 636 of the method 600 of FIG. 6B inaccordance with some embodiments. The step 636 is a CMOS-compatibleprocess flow.

Referring to FIG. 6D, the method 636 starts optionally at step 672 wherethe cap structure substrate is thinned. Step 672 is optional and dependson microneedle height(s). The cap structure substrate is thinned by anysuitable processes such as grinding and CMP. In the example shown inFIG. 27 , the cap structure substrate 230 is thinned by grinding the toppart of the cap structure 228.

The method 636 then proceeds to step 674. At step 674, hard mask(s) aredeposited at microneedle position(s). For simplicity, the situation ofone microneedle is described below. The hard mask at the microneedleposition can protect the microneedle position from subsequent etchingprocesses. In some embodiments, the hard mask may be formed of oxide. Insome embodiments, the hard mask may be formed of polysilicon. The hardmask is formed using suitable processes such as CVD and/or the like. Asshown in the example in FIG. 28 , the hard masks 237 (e.g., oxide hardmask) are deposited on the cap structure substrate 230 at themicroneedle position. The hard masks 237 may protect the microneedleposition from subsequent etching processes.

In one embodiment, the method 636 then proceeds to step 676 and step678. At step 676, the cap structure substrate is etched using isotropicetching and anisotropic etching in an alternate manner (i.e.,multiplexing). In other words, the etching process is switching betweenisotropic etching and anisotropic etching. Isotropic etching is anetching process that removes a material in multiple directions, andtherefore any horizontal components of the etch direction may result inundercutting of patterned areas. Anisotropic etching, on the other hand,is an etching process that aims to preferentially remove a material inspecific directions to obtain intricate and often flat shapes. In oneembodiment, the anisotropic etching used here is anisotropic deepreactive ion etching (DRIE) while the isotropic etching used here issulfur hexafluoride (SF₆) plasma etching. Specifically, the Boschprocess (i.e., pulsed or time-multiplexed etching) is used. In someembodiments, after the etching process, the apex of the microneedle issharpened by a final wet oxidation following by a consecutive oxidestrip. The oxidation is made with the hard mask still being on themicroneedle, which may result in a sharp apex. In the example shown inFIG. 29 , after step 676, the deep regions 239 are opened, and thechambers 244 can therefore be connected outside. A microneedle 241 isformed at the microneedle position.

The method 636 then proceeds to step 678, where the hard mask(s) areremoved. The hard mask is removed by any suitable processes. In oneembodiment, the hard mask is removed by wet etch. In some embodiments,the wet etch is a fluorine containing etch, such as dilute hydrofluoricacid (HF). In some embodiments, the wet etch is an ammoniahydroxide/hydrogen peroxide etch. As shown in the example in FIG. 30 ,the hard mask 237 shown in FIG. 29 is removed at step 678. The apex ofthe microneedle 241 is therefore exposed. As such, the microneedle 241is fabricated.

Alternatively in another embodiment, the method 636 may proceed to steps680, 682, and 684. At step 680, the cap structure substrate is etchedusing anisotropic etching by a predetermined depth. The predetermineddepth is approximate to a height of a microneedle. In one embodiment,the anisotropic etching used here is anisotropic deep reactive ionetching (DRIE). At step 682, the hard mask is removed. The hard mask isremoved by any suitable processes. In one embodiment, the hard mask isremoved by wet etch. In some embodiments, the wet etch is a fluorinecontaining etch, such as dilute hydrofluoric acid (HF). In someembodiments, the wet etch is an ammonia hydroxide/hydrogen peroxideetch. Then at step 684, the cap structure substrate is etched usingisotropic etching to form apex(es) of the microneedle(s). In someembodiments, the isotropic etching used here is sulfur hexafluoride(SF₆) plasma etching. The horizontal removal of the cap structuresubstrate 230 help form apex(es) of the microneedle(s).

In the example shown in FIG. 31 , after step 680, the deep regions 239,except the deep region 239 corresponding to the microneedle position,are opened, and the chambers 244 can therefore be connected outside. Inthe example shown in FIG. 32 , after step 682 and step 684, the hardmask 237 shown in FIG. 31 is removed at step 682. The top of themicroneedle 241 is therefore exposed. The top of the microneedle 241 isfurther sharpened to form the apex after step 684. As such, themicroneedle 241 is fabricated.

Referring to FIG. 6E, the method 636 shown in FIG. 6E applies torelatively long microneedles. Relatively long microneedles may bedesirable in certain applications. As shown in FIG. 6E, the method 636starts at step 691 where the cap structure substrate is thinned to openthe deep regions. The cap structure substrate is thinned by any suitableprocesses such as grinding and CMP. In the example shown in FIG. 33 ,the cap structure substrate 230 is thinned by grinding the top part ofthe cap structure 228. After step 691, the deep regions 239 are opened,and the chambers 244 can therefore be connected outside.

The method 636 then proceeds to step 692 where a second cap structure isfabricated and bonded to the cap structure. In the example shown in FIG.34 , a second cap structure 228′ is fabricated. The fabrication processof the second cap structure 228′ is similar to method 624 as shown inFIG. 6C, and therefore is not described in detail. The second capstructure 228′ has a deep region 239′ formed in a cap structuresubstrate 230′. A high-k dielectric material 242′ covers the top surfaceand sidewalls of the deep region 239′. In the example shown in FIG. 35 ,the second cap structure 228′ is bonded to the cap structure 228. Asmentioned above, the second cap structure 228′ may be bonded to the capstructure 228 using fusion bond, eutectic bond, anodic bond, and/orother suitable bonding methods. Alignment marks may be employed duringthe bonding process for alignment. As shown in FIG. 35 , the deep region239 and the deep region 239′ are aligned and form a relatively longneedle.

The method 636 then proceeds to step 693 where hard mask(s) aredeposited at microneedle position(s). In one embodiment, the method 636proceeds to step 694 and step 695. Alternatively in another embodiment,the method 636 may proceed to step 696, step 697, and step 698. Steps693-698 are similar to steps 674-684 of FIG. 6D, respectively, thereforeare not described in detail again. After implementing the method 636, arelatively long microneedle is fabricated.

Referring back to FIG. 6B, after microneedle(s) are created at the backside of the biosensor system package at step 636, the method 600 thenproceeds to step 638. At step 638, the biosensor system package 200 isdiced. In the example shown in FIG. 36 , the biosensor system package200 is diced by a dicing tool or saw, at the dashed lines shown in FIG.36 , to be separate from other neighboring components. Alignment marksmay be employed in the dicing process.

The method 600 then proceeds to step 640 where a separate chip isconnected to the biosensor system package through either wire bonding orthe TSV structure. The separate chip may be any chips that function as aportion of the biosensor system. In one embodiment, the separate chip isa RAM chip. In one embodiment, the separate chip is a data processingchip. In one embodiment, the separate chip is a RAM and data processingchip.

As shown in FIG. 37 , the biosensor system package 200 is connected to aseparate chip 250 through wire bonding. Wire bonding is a method ofmaking interconnections and is cost-effective and flexible. A metal(e.g., Al, Cu, Ag, or Au) wire 251 connects the separate chip 250 andthe conductive line 214 b in this example. As such, the biosensor systempackage 200 is fabricated using the method 600.

Alternatively as shown in FIG. 38 , the biosensor system package 200 isconnected to the separate chip 250 through the TSV structure formed atstep 632 above. The separate chip may be bonded to the TSV structure byany suitable processes. Compared with the wire bonding mentioned above,the connection through the TSV structure is a more compact solution andhas less resistance, capacitance, and inductance, which can achievefaster chip-to-chip data transmission with less noise, distortion, andpower consumption. In one embodiment, the separate chip is bonded to theTSV structure by solder bump bonding. Solder Bumps are the small spheresof solder (solder balls) that are bonded to contact areas or pads ofsemiconductor devices. In one example, the solder bump bonding includesthe following operations: placing solder bump(s) on the TSV structures;flipping the wafer; aligning the solder bump(s) with contact pad(s) ofthe separate chip; and reflowing the solder bump(s) in a furnace toestablish the bonding between the TSV structure and the separate chip.In other embodiments, the separate chip may be bonded to the TSVstructure by wire bonding. As shown in the example in FIG. 38 , theseparate chip 250 is bonded to the TSV structure 246 by solder bumpsbonding (using a solder bump 248). As such, the biosensor system package200 is fabricated using the method 600.

Embodiments in accordance with the disclosure include a biosensor systempackage. The biosensor system package includes: a transistor structurein a semiconductor layer having a front side and a back side, thetransistor structure comprising a channel region; a buried oxide (BOX)layer on the back side of the semiconductor layer, wherein the buriedoxide layer has an opening on the back side of the channel region, andan interface layer covers the back side over the channel region; amulti-layer interconnect (MLI) structure on the front side of thesemiconductor layer, the transistor structure being electricallyconnected to the MLI structure; and a cap structure attached to theburied oxide layer, the cap structure comprising a microneedle.

Further embodiments include a biosensor system package. The biosensorsystem package includes: a biosensor structure in a semiconductor layerhaving a front side and a back side, the biosensor structure comprisinga channel region and an interface layer covering the back side over thechannel region; a buried oxide (BOX) layer on the back side of thesemiconductor layer, wherein the buried oxide layer has an opening onthe back side of the channel region, and the interface layer is exposedin the opening; a multi-layer interconnect (MLI) structure on the frontside of the semiconductor layer, the biosensor structure beingelectrically connected to the MLI structure; a reference electrodeconnected to the MLI structure and configured to provide a referencepotential; and a cap structure attached to the buried oxide layer, thecap structure comprising a microneedle.

Further embodiments include a method of fabricating a biosensor systempackage. The method includes: providing a substrate, the substratecomprising a semiconductor layer having a front side and a back side, aburied oxide (BOX) layer at the back side, and a bulk silicon layer atthe back side; forming a transistor structure on the substrate, whereina channel region of the transistor structure is in the semiconductorlayer; forming a multi-layer interconnect (MLI) structure on the frontside of the semiconductor layer, wherein the MLI structure iselectrically connected to the transistor structure; attaching a carriersubstrate to the MLI structure; removing the bulk silicon layer; etchingthe buried oxide layer to form an opening at the back side over thechannel region; depositing an interface layer on the back side over thechannel region; fabricating a cap structure using a complementarymetal-oxide-semiconductor (CMOS) compatible process flow; bonding thecap structure to the BOX layer; and creating a microneedle on the capstructure.

The foregoing outlines features of several embodiments so that thoseskilled in the art may better understand the aspects of the presentdisclosure. Those skilled in the art should appreciate that they mayreadily use the present disclosure as a basis for designing or modifyingother processes and structures for carrying out the same purposes and/orachieving the same advantages of the embodiments introduced herein.Those skilled in the art should also realize that such equivalentconstructions do not depart from the spirit and scope of the presentdisclosure, and that they may make various changes, substitutions, andalterations herein without departing from the spirit and scope of thepresent disclosure.

1-20. (canceled)
 21. A biosensor system package comprising: a transistorstructure in a semiconductor layer having a front side and a back side,the transistor structure comprising a channel region; a buried oxide(BOX) layer on the back side of the semiconductor layer, wherein theburied oxide layer has an opening on the back side of the channelregion, and an interface layer covers the back side over the channelregion; a multi-layer interconnect (MLI) structure on the front side ofthe semiconductor layer, the transistor structure being electricallyconnected to the MLI structure; a carrier substrate on the MLIstructure; a through substrate via (TSV) structure extending though thecarrier substrate and configured to provide an electrical connectionbetween the MLI structure and a first separate die; and a cap structureattached to the buried oxide layer, the cap structure comprising amicroneedle.
 22. The biosensor system package of claim 21, wherein theTSV structure comprises: a conductive material; a liner isolating theconductive material from the carrier substrate; and a diffusion barrierlayer between the conductive material and the liner.
 23. The biosensorsystem package of claim 21, further comprising: the first separate die,wherein the first separate die is electrically connected to the TSVstructure and configured to process data collected by the transistorstructure.
 24. The biosensor system package of claim 21, wherein the capstructure further comprises: a cap structure substrate having a chamberconfigured to accommodate fluid samples to be tested, and wherein themicroneedle relates to the chamber for inflow and outflow of the fluidsamples.
 25. The biosensor system package of claim 24, wherein the capstructure further comprises: a high-k dielectric material layer coveringa bottom and sidewalls of the chamber.
 26. The biosensor system packageof claim 24, wherein the cap structure substrate has bonding areasinterfacing with bonding sites of the buried oxide layer.
 27. Thebiosensor system package of claim 24, wherein the interface layercomprises a layer of capture reagent capable of binding a target analytein the fluid samples.
 28. The biosensor system package of claim 21,further comprising: a reference electrode connected to the MLI structureand configured to provide a reference potential.
 29. The biosensorsystem package of claim 21, wherein the interface layer is a high-kmaterial layer.
 30. A biosensor system package comprising: a transistorstructure in a semiconductor layer having a front side and a back side,the transistor structure comprising a channel region; a buried oxide(BOX) layer on the back side of the semiconductor layer, wherein theburied oxide layer has an opening on the back side of the channelregion, and an interface layer covers the back side over the channelregion; a multi-layer interconnect (MLI) structure on the front side ofthe semiconductor layer, the transistor structure being electricallyconnected to the MLI structure; a wire bonding opening through theburied oxide layer, the semiconductor layer, and the MLI structure, andwherein a first conductive line in a first metal (M1) layer of the MLIstructure is exposed in the wire bonding opening; and a cap structureattached to the buried oxide layer, the cap structure comprising amicroneedle.
 31. The biosensor system package of claim 30, wherein thefirst conductive line is electrically connected to a second separate dieby wire bonding.
 32. The biosensor system package of claim 30, whereinthe cap structure further comprises: a cap structure substrate having achamber configured to accommodate fluid samples to be tested, andwherein the microneedle relates to the chamber for inflow and outflow ofthe fluid samples.
 33. The biosensor system package of claim 30, furthercomprising: a temperature sensor formed in the semiconductor layer. 34.The biosensor system package of claim 30, further comprising: areference electrode connected to the MLI structure and configured toprovide a reference potential.
 35. The biosensor system package of claim30, further comprising: an electric-resistive heater comprising a secondconductive line in a layer of the MLI structure.
 36. A biosensor systempackage comprising: a biosensor structure in a semiconductor layerhaving a front side and a back side, the biosensor structure comprisinga channel region and an interface layer covering the back side over thechannel region; a buried oxide (BOX) layer on the back side of thesemiconductor layer, wherein the buried oxide layer has an opening onthe back side of the channel region, and the interface layer is exposedin the opening; a multi-layer interconnect (MLI) structure on the frontside of the semiconductor layer, the biosensor structure beingelectrically connected to the MLI structure; a carrier substrate on theMLI structure; a through substrate via (TSV) structure extending thoughthe carrier substrate and configured to provide an electrical connectionbetween the MLI structure and a first separate die; a referenceelectrode connected to the MLI structure and configured to provide areference potential; and a cap structure attached to the buried oxidelayer, the cap structure comprising a microneedle.
 37. The biosensorsystem package of claim 36, wherein the TSV structure comprises: aconductive material; a liner isolating the conductive material from thecarrier substrate; and a diffusion barrier layer between the conductivematerial and the liner.
 38. The biosensor system package of claim 36,further comprising: the first separate die, wherein the first separatedie is electrically connected to the TSV structure and configured toprocess data collected by the transistor structure.
 39. The biosensorsystem package of claim 36, further comprising: a temperature sensorformed in the semiconductor layer; and an electric-resistive heatercomprising a conductive line in a first metal (M1) layer of the MLIstructure.
 40. The biosensor system package of claim 36, wherein the MLIstructure comprises: a plurality of interposing dielectric layers; aplurality of conductive lines, each conductive line disposed in one ofthe plurality of interposing dielectric layers; and a plurality ofconductive interconnect access (VIA) structures connecting the pluralityof conductive lines.